Hereditary Disorders Of Connective Tissue--Clinical And Molecular Studies

本研究检查了结缔组织遗传性疾病的临床特征以及分子和生化相关性;马凡氏综合征，Ehlers-Danlos综合征（EDS）和Stickler综合征，以及相关疾病，如家族性动脉瘤综合征和纤维肌肉发育不良。迄今为止，约有650例受试者入组本研究。 根据霍尔特监测数据和血压测量的频域分析，在30%的EDS受试者中记录了自主神经功能障碍伴交感神经张力增加和体位性心动过速。骨密度测定研究表明，过早骨质疏松和骨量减少在EDS和Marfan患者中非常常见，并可能与特定的突变相关。还对受试者进行颈椎和腰椎的MRI研究。我们最近发现，大约三分之一的患者有基亚里I畸形，85%的受试者有与脊柱相关的显著异常，包括椎间盘突出、脊椎滑脱和硬脑膜扩张。我们注意到以前未被认识到的EDS并发症，包括老年EDS患者（我们队列的15%）发生类风湿性关节炎，临床显著睡眠障碍的发生率增加，以及与所有年龄组的NHANES平均值相比，不良血脂谱的患病率很高。内分泌异常HDCT进行了分析。大约30%的血管性EDS和马凡氏综合征的男性有性腺功能减退症，并伴有低骨密度。我们已经确定了一个家族性动脉瘤家族，其表型与COL 5A 1中的提前终止密码子分离。在入组研究的受试者中发现了一种先前未被识别的结缔组织遗传性疾病，即具有结缔组织特征的纤维肌性发育不良（FMD）。 在结缔组织队列中，并发症如脊柱椎间盘疾病、血管脆性、性腺衰竭、干密度丧失、慢性疼痛和肌肉骨骼损伤出现在更年轻的年龄。从这项研究中获得的信息不仅有助于治疗受影响的患者，而且还将提供对正常衰老病理过程的见解。

This study examines the clinical features as well as molecular and biochemical correlates of heritable disorders of connective tissue; Marfan Syndrome, Ehlers-Danlos Syndrome (EDS) and Stickler Syndrome, as well as related disorders such as Familial Aneurysm Syndromes and Fibromuscular Dysplasia. To date, approximately 650 subjects have been enrolled in the study. Autonomic dysfunction with increased sympathetic tone and post orthostatic tachycardia has been documented in 30% of the subjects with EDS, based on frequency domain analysis of the Holter monitor data and blood pressure measurements. Bone densitometry studies have shown that premature osteoporosis and osteopenia are very common in the EDS and Marfan patients, and may be correlated with specific mutations. MRI studies of the cervical and lumbar spine are also carried out on subjects. We have recently found that approximately one third of patients have Chiari I malformations and 85% of the subjects have significant abnormalities pertaining to the spine including hernitated discs, spondylolisthesis, and dural ectasia. We have noted previously unrecognized complications of EDS, including the development of rheumatoid arthritis in older persons with EDS (in 15% of our cohort), increased incidence of clinically significant sleep disorders, and a high prevalence of unfavorable lipid profiles as compared to NHANES averages in all age groups. Endocrine abnormalities in HDCT have been analyzed. Approximately 30% of the males with Vascular EDS and Marfan syndrome have hypogonadism and accompanying low bone density. We have identified a Familial Aneurysm family where the phenotype segregates with a premature stop codon in COL5A1. A previously unrecognized hereditary disorder of connective tissue, fibromuscular dysplasia (FMD) with connective tissue features has been identified within subjects enrolled in the study. In the connective tissue cohort, complications such as disc disease in the spine, vascular fragility, gonadal failure, done density loss, chronic pain and musculoskeletal impairment appear at a much younger age. The information obtained from this study will not only help the treatment of effected patients, but will also provide insights into the pathological processes of normal aging.